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UseCase1 Fluoroacetate
Example of mechanistic inhibition
Sodium fluroacetate is a metabolic poison found it over 40 plants in Australia, Brazil, and Africa. Symptoms of fluroacetate poisoning begins after 30 min from exposure and include nausea, vomiting, stomach pain, sweating and confusion.
Fluroacetate, an analog of acetate , is coupled to CoA to form fluroacetyl-CoA by acetate thiokinase -{Voet 2003}-. Fluroacetyl-CoA is converted to yield 2-flurocitrate through a condensation reaction with oxaloacetate. The (-)-erythro diastereomer ((2R,3R)-2-flurocitrate) of 2-flurocitrate is then converted to fluoro-cis-aconitate, which is followed by addition of hydroxide and with loss of a fluoride atom to form 4-hydroxy-trans-aconitate (HTn), which binds tightly, but not covalently to the enzyme -{Lauble 1996, Boelsterli 2003}-. Binding of 4-hydroxy-trans-aconitate results in inhibition of aconitase enzyme followed by inhibition of the citric acid cycle.
Representational Biochemical
1. Chemical derivatives and variants
Expression(language requirements)
Functional (Question and Answer) Q. “Which mechanism involve inhibition of aconitase?” A. “The mechanism of aconitase inhibition by fluroacetate” Query: ‘mechanism of protein inhibition’ and ‘has part’ some (inhibition and realizes some (‘to be inhibited’ that ‘is disposition of’ some aconitase)) Q. “Which mechanism involves 2-flurocitrate?” A. “The mechanism of aconitase inhibition by fluroacetate” Query: Q. “What pathway does this mechanism alter?” A. “This mechanism alters the citric acid pathway” Query: Q. “Does this mechanism involve inhibition?” A. “Yes, inhibition of aconitase” Query:
The following mechanism of comprised of 4 distinct subprocesses: 1. Fluroacetate is conjugated with coenzyme a to form fluoroacetyl-CoA. This reaction is catalysed by the enzyme acetate thiokinase. 2. Fluoroacetyl-CoA is converted to 2-Fluorocitrate. However, it is the specific disatereomer (2R,3R)-2-fluorocitrate that will go on to inhibit aconitase. This reaction is catalyzed by citrate synthase. 3. (2R,3R)-2-Fluorocitrate is converted fluoro-cis-aconitate. The reaction is catalyzed by aconitase. 4. Fluoro-cis-aconitate is converted to 4-hydroxy-trans-aconitate. The reaction is catalyzed by aconitase. 5. 4-hydroxy-trans-aconitate non-covalently binds to aconitase inhibiting function.
fluoroacetate subClassOf ‘chemical entity’ that ‘is target in’ some ‘enzymatic conjugation of fluoroacetate and coenzyme a’ fluoroacetyle-CoA subClassOf ‘chemical entity’ that ‘is product in’ some ‘enzymatic conjugation of fluoroacetate and coenzyme a’ ‘coenzyme a’ subClassOf ‘chemical entity’ ‘acetate thiokinase’ subClassOf ‘protein that ’has disposition’ some (‘to covalently modify’ and ‘has target’ some ‘fluoroacetate’ ) and ‘is realized in’ only ‘enzymatic conversion of ’enzymatic conjugation of fluoroacetate and coenzyme a’) that ‘has disposition’ some (‘to covalently modify’ that ‘has target’ some ‘coenzyme a’) and ‘is realized in’ only ‘enzymatic conversion of ’enzymatic conjugation of fluoroacetate and coenzyme a’) ‘enzymatic conjugation of fluoroacetate and coenzyme a’ subClassOf ‘biochemical reaction’ that ‘has target’ some ‘fluoroactate’ that ‘has target’ some ‘coenzyme a’ that ‘has agent’ some ‘acetate thiokinase’ that ‘has product’ some ‘fluoroacetyl-CoA’ and ‘realizes’ some (‘to covalently modify’ that ‘is disposition of’ some ‘acetate thiokinase’)
Process 2: Enzymatic Conversion of Fluoroacetyl-CoA to (2R,3R)-2-Fluorocitrate by citrate synthase¶ ↑
The example below details the process of enzymatic conversion of fluoroacetyl-CoA to a specific disastereomer (2R,3R)-2-Fluorocitrate.
‘citrate synthase’ subClassOf ‘protein’ that ‘has disposition’ some (‘to covalently modify’ that ‘has target’ some fluoroacetyl-CoA ) and ‘is realized in’ only ‘enzymatic conversion of fluoroacetyl-CoA to (2R,3R)-2-Flurocitrate’) fluoroacetyl-CoA subClassOf ‘chemical complex’
(2R,3R)-2-Fluorocitrate subClassOf ‘chemical entity’
‘enzymatic conversion of fluoroacetyl-CoA to (2R,3R)-2-Fluorocitrate’ subClassOf ‘biochemical reaction’ that ‘has target some ’oxaloacetate(2-)‘ and ’has target some ‘fluoroacetyl-CoA and ’has agent’ some ‘citrate syntase’ and ‘has product’ some ‘(2R,3R)-2-fluorocitrate’ and ‘realizes’ some (‘to covalently modify’ that ‘is disposition of’ some ‘citrate synthase’)
The example below details the conversion of (2R,3R)-2-Fluorocitrate to fluoro-cis-aconitate by the enzyme aconitase.
‘aconitase’ subClassOf ‘protein that ’has disposition’ some (‘to covalently modify’ that ‘has target’ some ‘(2R,3R)-2-fluorocitrate’) and ‘is realized in’ only ‘enzymatic conversion of (2R,3R)-2-fluorocitrate to fluoro-cis-aconitate’)
fluoro-cis-aconitate subClassOf ‘chemical entity’
‘Enzymatic conversion of (2R,3R)-2-Fluorocitrate to fluoro-cis-aconitate’ subClassOf ‘biochemical reaction’ that ‘has target’ some ‘(2R,3R)-2-Fluorocitrate’ and ‘has agent’ some ‘aconitase’ and ‘has product’ some ‘fluoro-cis-aconitate’ and ‘realizes’ some (‘to covalently modify’ that ‘is disposition of’ some ‘aconitase’)
‘aconitase’ subClassOf protein that ‘has disposition’ some (‘to covalently modify’ that ‘has target’ some fluoro-cis-aconitate) that ‘is realized in’ only ‘enzymatic conversion of fluoro-cis-aconitate to 4-hydroxy-trans-aconitate’
fluoro-cis-aconitate subClassOf ‘chemical entity’
‘Enzymatic conversion of fluoro-cis-aconitate to 4-hydroxy-trans-aconitate’ subClassOf ‘biochemical reaction’ that ‘has target’ some ‘fluoro-cis-aconitate’) and ‘has agent’ some ‘aconitase’) and ‘has product’ some ‘4-hydroxy-trans-aconitate’) and ‘realizes’ some (‘to covalently modify’ that ‘is disposition of’ some ‘aconitase’)
‘aconitase’ subClassOf protein that ‘has disposition’ some ‘to be inhibited’ that ‘is realized in’ only ‘4-hydroxy-trans-aconitate bound to aconitase’ ‘4-hydroxy-trans-aconitate subClassOf ’chemical entity’ ‘4-hydroxy-trans-aconitate aconitase complex formation’ subClassOf ‘molecular complex formation’ that ‘has target’ some ‘4-hydroxy-trans-aconitate and ’has target’ some ‘aconitase’ and ‘has product’ some ‘4-hydroxy-trans-aconitate aconitase complex’ and ‘realizes’ some (‘to bind’ that ‘is disposition of’ some aconitase) and ‘realizes’ some (‘to bind’ that ‘is disposition of’ some 4-hydroxy-trans-aconitate) and ‘realizes’ some (‘to inhibit’ that ‘is disposition of’ some 4-hydroxy-trans-aconitate) and ‘results in’ some ‘aconitase inhibition’
The descriptions of the above allow a description of the mechanistic based inhibition of aconitase by fluoroacetate. This is achieved through linking the processes together in temporal order. ‘aconitase inhibition’ subClassOf ‘protein inhibition’ that ( realizes some (‘to be inhibited’ that ‘is disposition of’ some aconitase)) and ‘results in’ some ‘citric acid cycle inhibition’ ‘citric acid cycle inhibition’ subClassOf ‘pathway inhibition’ that ‘results in’ some ‘cellular energy depletion’ ‘mechansim of aconitase inhibition by fluroacetate’ subClassOf ‘mechanism of aconitase inhibition’ that ‘has proper part’ some ‘enzymatic conversion of fluoroacetate to fluoroacetyl-CoA’ and preceds some ‘enzymatic conversion of fluoroacetyl-CoA to (2R,3R)-2-Flurocitrate’ and preceds some ‘enzymatic conversion of (2R,3R)-2-fluorocitrate to fluoro-cis-aconitate’ and preceds some ‘enzymatic conversion of fluoro-cis-aconitate to 4-hydroxy-trans-aconitate’ and preceds some ‘4-hydroxy-trans-aconitate bound to aconitase’
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